Two major health issues facing women as they age are cardiovascular disease (CVD) and menopausal hot flashes. CVD is the leading cause of death among women. Hot flashes are experienced by many midlife women, and for 30% of women, they are frequent or severe. Although hot flashes are traditionally regarded as a benign midlife symptom, recent research has linked a high burden of hot flashes to CVD risk. Several large trials have indicated that the greatest risk of cardiovascular events with hormone use appears concentrated among women reporting moderate to severe hot flashes. Our research shows elevated subclinical CVD among women reporting frequent hot flashes. Important mechanisms linking a high burden of hot flashes to CVD risk may be changes in endothelial function, inflammation/coagulation and cardiac vagal control. However, findings linking hot flashes to cardiovascular risk are just emerging. None of these studies was designed to examine associations between hot flashes and cardiovascular risk. Most have notable limitations, including the reliance upon crude, self-report measures of hot flashes vulnerable to multiple biases. The aim of this investigation is to examine whether women with daily hot flashes have adverse indicators of cardiovascular risk, including poorer endothelial function, higher carotid intima media thickness, lower cardiac vagal control, and an adverse inflammatory and hemostatic profile, relative to women without hot flashes. It is hypothesized that these differences will be independent of traditional CVD risk factors. Secondary aims include testing acute changes in cardiac vagal control during hot flashes and examining key pathways involved in these associations. The proposed sample includes 300 perimenopausal and postmenopausal women aged 40-60, half with daily hot flashes and half without hot flashes. Participants will be nonsmokers, free of heart disease and treated diabetes or hypertension, and free of medications impacting hot flashes. All women will undergo 3 days of physiologic hot flash monitoring, 24 hours of which will include ambulatory electrocardiography for measurement of cardiac vagal control (high frequency heart rate variability), a brachial artery ultrasound for measurement of endothelial function (flow mediated dilation), a carotid artery ultrasound for measurement of intima media thickness, and a blood sample for assessment of inflammatory/hemostatic markers and estradiol concentrations. Relations between hot flashes and cardiovascular risk indicators will be examined using linear regression and linear mixed models. This study represents the first study specifically designed to examine relations between hot flashes and CVD risk, and is an important first step in better understanding links between hot flashes and CVD risk. Addressing these aims may inform a better understanding of the physiology of hot flashes and support the development of a novel marker of cardiovascular risk among midlife women. This work has the potential to challenge the way that this presumably benign menopausal symptom is understood by researchers, clinicians, and women. PUBLIC HEALTH RELEVANCE: This research is aimed at understanding whether and how menopausal hot flashes are linked to cardiovascular disease (CVD) risk. This work has the potential to change the way that this common midlife symptom has long been understood. This research may ultimately assist with CVD risk prediction among midlife women.